Crystal of pyrrole derivative and method for producing the same

ABSTRACT

The present invention provides a production intermediate of an atropisomer of a pyrrole derivative having excellent mineralocorticoid receptor antagonistic activity, a method for producing the same, and a crystal thereof. A method for producing an atropisomer of a pyrrole derivative including a step of resolving a compound represented by the following general formula (I) [wherein R 1  represents a methyl group or a trifluoromethyl group, R 2  represents a hydrogen atom or a C1-C3 alkoxy group, and n represents an integer selected from 1 to 3] into its atropisomers, characterized by using an optically active amine having a cinchonine skeletal formula, and a crystal of (S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide.

TECHNICAL FIELD

The present invention relates to a crystal of an atropisomer of apyrrole derivative having excellent mineralocorticoid receptorantagonistic activity, a method for producing the same, and a productionintermediate thereof.

BACKGROUND ART

The mineralocorticoid receptor (MR) (aldosterone receptor) is known toplay an important role in regulating electrolyte balance and bloodpressure in the body. For example, MR antagonists such as spironolactoneand eplerenone, both of which have a steroidal structure, are known tobe useful for the treatment of hypertension and heart failure.

A pyrrole derivative having excellent mineralocorticoid receptorantagonistic activity is disclosed in PTL 1 and PTL 2 and is known to beuseful for the treatment of hypertension, angina pectoris, acutecoronary syndrome, congestive heart failure, nephropathy,arteriosclerosis, cerebral infarction, fibrosis, primary aldosteronism,or a heart disease (particularly, hypertension or diabetic nephropathy).

CITATION LIST Patent Literature

PTL 1: WO 2006/012642 (US Publication No. US 2008-0234270)

PTL 2: WO 2008/056907 (US Publication No. US 2010-0093826)

SUMMARY OF INVENTION Technical Problem

A substance to be used for a pharmaceutical product is required to havestrictly high purity so as not to cause unpredicted side effects (forexample, toxicity, etc.) due to its impurities. Further, in itsindustrial production method (mass production method), impurities arerequired to be removed by a simpler operation.

In addition, it is important that a pharmaceutical drug substance can bestored for a long period of time while maintaining its quality. In thecase where it is necessary to store a pharmaceutical drug substanceunder low temperature conditions, a large-scale refrigeration facilityis needed for maintaining quality, and therefore, it is industriallymeaningful to find a stable crystal which can be stored at roomtemperature or higher.

Under such circumstances, the present inventors made intensive studiesfor developing a method for producing a pyrrole derivative havingexcellent MR antagonistic activity with higher quality in higher yieldby using a more industrially advantageous operation method with lowerenvironmental impact. As a result, they found a method for efficientresolution of an atropisomer of a novel synthetic intermediate, andbased on this finding, they established a method for producing a pyrrolederivative with high quality in high yield by using an industriallyadvantageous operation, and thus completed the present invention.

Solution to Problem

The present inventors intensively studied a crystal of an atropisomer ofa pyrrole derivative, a production intermediate thereof, and anefficient method for producing the same so as to improve solubility,purity, stability, and the like for enhancing the medical usefulness ofan atropisomer of a pyrrole derivative having excellentmineralocorticoid receptor antagonistic activity.

Hereinafter, the present invention will be described in detail.

The present invention is directed to:

(1) a method for resolving a compound represented by the followinggeneral formula (I):

[wherein R¹ represents a methyl group or a trifluoromethyl group, R²represents a hydrogen atom or a C1-C3 alkoxy group, and n represents aninteger selected from 1 to 3] into its atropisomers, characterized byusing an optically active amine having a cinchonine skeletal formula;

(2) the method according to the above (1), wherein the optically activeamine is one compound selected from the group of compounds representedby the following formulae:

(3) the method according to the above (1), wherein the optically activeamine is quinine represented by the following formula:

(4) the method according to any one of the above (1) to (3), wherein themethod is performed in an organic solvent or a mixed solvent of anorganic solvent and water;

(5) the method according to any one of the above (1) to (4), wherein thecompound represented by the general formula (I) is the followingcompound (Ia):

(6) a method for producing(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamiderepresented by the following formula (A):

characterized by obtaining one atropisomer of(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid represented by the following formula (Ia):

by resolution using an optically active amine having a cinchonineskeletal formula, removing the optically active amine under acidicconditions, followed by reaction with oxalyl chloride, thereby formingthe following intermediate compound (IIa):

and then further reacting the intermediate compound (IIa) with4-(methylsulfonyl)aniline, thereby forming the following intermediatecompound (IIIa):

followed by a base treatment;

(6-1) the production method according to the above (6), wherein thereaction temperature during the reaction with oxalyl chloride forobtaining the intermediate compound (IIa) and during the reactionbetween the intermediate compound (IIa) and 4-(methylsulfonyl)aniline is20° C. or lower;

(6-2) the production method according to the above (6), wherein themethod includes a step of isolating the intermediate compound (IIIa);

(6-3) the production method according to the above (6), wherein the oneatropisomer of(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid is(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid;

(7)(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid represented by the following formula (Ia):

which is an intermediate for producing(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamiderepresented by the following formula (A):

(8) an optically active amine salt (the optically active amine is onecompound selected from cinchonine, quinine, cinchonidine, and quinidine)of a compound represented by the following general formula (I):

[wherein R¹ represents a methyl group or a trifluoromethyl group, R²represents a hydrogen atom or a C1-C3 alkoxy group, and n represents aninteger selected from 1 to 3];

(8-1)(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid quinine salt;

(9) a crystal of(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamiderepresented by the above formula (A), which shows characteristic peaksat diffraction angles 2θ of 6.80, 17.06, 19.24, 22.80, and 25.48 in apowder X-ray diffraction pattern obtained by irradiation with copper Kαradiation (wavelength λ=1.54 Å);

(10) a crystal of(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamiderepresented by the above formula (A), which shows main peaks atdiffraction angles 2θ of 6.80, 12.32, 13.60, 14.46, 16.30, 17.06, 18.42,19.24, 19.86, 20.36, 20.82, 21.84, 22.50, 22.80, 23.20, 23.50, 24.60,24.88, 25.48, 26.96, 27.52, 29.26, 31.80, 32.08, 35.82, 40.32, and 41.36in a powder X-ray diffraction pattern obtained by irradiation withcopper Kα radiation (wavelength λ=1.54 Å);

(10-1) a crystal of(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,which has the X-ray diffraction pattern shown in FIG. 1 in a powderX-ray diffraction pattern obtained by irradiation with copper Kαradiation (wavelength λ=1.54 Å);

(11) a pharmaceutical composition, containing the crystal according tothe above (9) or (10) as an active ingredient;

(12) a prophylactic or therapeutic agent for hypertension, anginapectoris, acute coronary syndrome, congestive heart failure,nephropathy, arteriosclerosis, cerebral infarction, fibrosis, primaryaldosteronism, or a heart disease, containing the crystal according tothe above (9) or (10) as an active ingredient;

(13) a prophylactic or therapeutic agent for hypertension, containingthe crystal according to the above (9) or (10) as an active ingredient;

(13-1) a therapeutic agent for hypertension, containing the crystalaccording to the above (9) or (10) as an active ingredient;

(14) a prophylactic or therapeutic agent for diabetic nephropathy,containing the crystal according to the above (9) or (10) as an activeingredient;

(14-1) a therapeutic agent for diabetic nephropathy, containing thecrystal according to the above (9) or (10) as an active ingredient;

(15) use of the crystal according to any one of the above (9) or (10)for producing a medicament;

(16) use of the crystal according to the above (9) or (10) for producinga medicament for preventing or treating hypertension, angina pectoris,acute coronary syndrome, congestive heart failure, nephropathy,arteriosclerosis, cerebral infarction, fibrosis, primary aldosteronism,or a heart disease;

(17) use of the crystal according to the above (9) or (10) for producinga medicament for treating hypertension; and

(18) use of the crystal according to the above (9) or (10) for producinga medicament for treating diabetic nephropathy.

(S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamiderepresented by the following formula (A):

is sometimes referred to as Compound (A) in this description.

In the present invention, “crystal” refers to a solid whose internalstructure is three-dimensionally composed of a regular repetition ofconstituent atoms (or a group thereof), and is distinguished from anamorphous solid which does not have such a regular internal structure.

The crystal of the present invention may sometimes form a hydrate byallowing the crystal to stand in the air to absorb water, thereby havingattached water, or by heating the crystal to 25 to 150° C. in usualatmospheric conditions, etc. Further, the crystal of the presentinvention may sometimes contain a solvent used at the time ofcrystallization in an attached residual solvent or a solvate.

In this description, the crystal of the present invention is sometimesrepresented on the basis of powder X-ray diffraction data. In the powderX-ray diffraction, measurement and analysis may be performed by a methodconventionally used in this field, and for example, the powder X-raydiffraction can be performed by a method described in the Examples.Further, in general, in the case of a hydrated or dehydrated crystal,the lattice constant thereof is changed by the addition or removal ofwater of crystallization, and therefore the diffraction angle (2θ) inpowder X-ray diffraction may sometimes be changed. Further, the peakintensity may sometimes be changed due to a difference in a crystalgrowth surface or the like (crystal habit), etc. Therefore, when thecrystal of the present invention is represented on the basis of powderX-ray diffraction data, a crystal having identical peak diffractionangles and X-ray diffraction pattern in powder X-ray diffraction, andalso hydrated and dehydrated crystals obtained from the crystal are alsoencompassed within the scope of the present invention.

One preferred embodiment of the crystal of the present invention is acrystal of a pyrrole derivative compound (A). The crystal of Compound(A) has the X-ray diffraction pattern shown in FIG. 1 in a powder X-raydiffraction pattern obtained by irradiation with copper Kα radiation(wavelength λ=1.54 Å). Further, the crystal of Compound (A) hascharacteristic peaks at diffraction angles 2θ of 6.80, 17.06, 19.24,22.80, and 25.48 in a powder X-ray diffraction pattern obtained byirradiation with copper Kα radiation (wavelength λ=1.54 Å). Here,“characteristic peak” refers to a peak having a relative intensity of 50or more when the maximum peak intensity in the powder X-ray diffractionpattern is taken as 100. Further, the crystal of Compound (A) of thepresent invention is also a crystal which shows main peaks atdiffraction angles 2θ of 6.80, 12.32, 13.60, 14.46, 16.30, 17.06, 18.42,19.24, 19.86, 20.36, 20.82, 21.84, 22.50, 22.80, 23.20, 23.50, 24.60,24.88, 25.48, 26.96, 27.52, 29.26, 31.80, 32.08, 35.82, 40.32, and 41.36in a powder X-ray diffraction pattern obtained by irradiation withcopper Kα radiation (wavelength λ=1.54 Å). Here, “main peak” refers to apeak having a relative intensity of 15 or more when the maximum peakintensity in the powder X-ray diffraction pattern is taken as 100.

In the present invention, examples of the “C1-C3 alkoxy group” includemethoxy, ethoxy, propoxy, and isopropoxy groups. Preferred examplesthereof for R² include a methoxy group.

R² is preferably a hydrogen atom or a C1-C4 alkoxy group, morepreferably a hydrogen atom or a methoxy group, and particularlypreferably a hydrogen atom.

n is preferably 2.

A compound represented by the following formula (I):

[wherein R¹ represents a methyl group or a trifluoromethyl group, R²represents a hydrogen atom or a C1-C3 alkoxy group, and n represents aninteger selected from 1 to 3] is preferably(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxicacid represented by the following formula (Ia):

or(RS)-1-(2-hydroxyethyl)-4-methyl-5-[4-methoxy-2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxicacid, and more preferably(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxicacid.

A method for producing a pyrrole derivative compound (A′) using theproduction intermediate compound of the present invention will bedescribed in detail below.

The pyrrole derivative compound (A′) can be produced by using a knowncompound as a starting material and using the following productionmethod of the present invention and intermediates. Incidentally, in thefollowing description, R¹, R², and n represent the same meanings asdescribed above, respectively.

Step A: Production of Intermediate Compound (I)

Step B: Production of Pyrrole Derivative Compound (A′)

Hereinafter, the respective steps will be described.

(Step A-1)

This step is a step of producing Compound (VII) by reacting Compound(VIII) with ethyl cyanoacetate in the presence of a base.

The starting material is preferably2-bromo-1-[2-(trifluoromethyl)phenyl]propan-1-one.

As a solvent, an organic solvent which does not inhibit the reaction anddissolves the starting material to some extent is used. The solvent ispreferably an amide, more preferably N,N-dimethylacetamide.

The base is preferably a metal hydride such as sodium hydride or analkali metal carbonate such as potassium carbonate, more preferablypotassium carbonate.

The reaction temperature is from 0° C. to 100° C., preferably from 40°C. to 60° C.

The reaction time is from 0.5 to 12 hours, preferably 1 to 3 hours.

(Step A-2)

This step is a step of producing Compound (VI) by cyclizing Compound(VII) to form a pyrrole ring.

As a solvent, an organic solvent which does not inhibit the reaction anddissolves the starting material to some extent is used. The solvent ispreferably an ether such as tetrahydrofuran, an aromatic hydrocarbonsuch as toluene, or an ester such as ethyl acetate, more preferablyethyl acetate or tetrahydrofuran, particularly preferably ethyl acetate.

As a reagent, it is preferred to blow hydrogen chloride gas in thepresence of thionyl chloride, and further concentrated sulfuric acid maybe added.

The reaction temperature is from 0° C. to 40° C., preferably roomtemperature.

The reaction time is from 1 to 30 hours, preferably 10 to 20 hours.

(Step A-3)

This step is a step of producing Compound (V) by removing a chlorinegroup of Compound (VI).

As a solvent, a mixed solvent of water and an organic solvent which doesnot inhibit the reaction and dissolves the starting material to someextent is used. The solvent is preferably a mixed solvent of ethanol,tetrahydrofuran, and water.

As a reagent, sodium formate and a 5% palladium-carbon catalyst arepreferred.

The reaction temperature is from 0° C. to 100° C., preferably from 40°C. to 60° C.

The reaction time is from 0.5 to 12 hours, preferably 0.5 to 2 hours.

(Step A-4)

This step is a step of producing Compound (IV) by introducing a hydroxyC1-3 alkyl group on the nitrogen atom of the pyrrole group of Compound(V) in a solvent in the presence of a base.

As the solvent, an organic solvent which does not inhibit the reactionand dissolves the starting material to some extent is used. The solventis preferably an amide such as N,N-dimethylacetamide.

The base is preferably a metal alkoxide such as t-butoxy potassium ort-butoxy sodium or an organic base such as 4-dimethylaminopyridine, morepreferably 4-dimethylaminopyridine.

The reagent for introducing a hydroxyalkyl group is preferably2-iodoethanol, 2-bromoethanol, or ethylene carbonate, more preferablyethylene carbonate.

The reaction temperature is from room temperature to 150° C., preferablyfrom 100° C. to 120° C.

The reaction time is from 1 to 20 hours, preferably 5 to 15 hours.

(Step A-5)

This step is a step of obtaining Compound (I) by alkaline hydrolysis ofan ester of Compound (IV).

This step is usually performed in a solvent. The solvent is preferably amixed solvent of water and an alcohol such as ethanol.

The reagent is not particularly limited as long as it is a basic reagentwhich hydrolyzes a carboxylate ester, but is preferably sodiumhydroxide.

The reaction temperature is from room temperature to 100° C., preferablyfrom 50° C. to 80° C.

The reaction time is from 1 to 20 hours, preferably 5 to 10 hours.

In one embodiment, Compound (Ia),(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid, is prepared from ethyl2-chloro-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate(see Example 3) in three steps, as described in Examples 13-15.

Briefly, ethyl2-chloro-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylateis treated with ethylene carbonate under standard N-alkylatingconditions (e.g., suitable base and solvent) to provide ethyl(RS)-2-chloro-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate(see Example 13).

In the second step, ethyl(RS)-2-chloro-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylateis dechlorinated using a suitable reagent (e.g., 5% palladium-carboncatalyst) under suitable dechlorination conditions (e.g., water,ethanol, sodium formate) to provide ethyl (RS)-1-(2-hydroxyethyl)4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (SeeExample 14).

In the third step, ethyl(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylateis converted to(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid, the corresponding acid, by hydrolysis under standard esterhydrolysis conditions (e.g., aqueous sodium hydroxide) followed byisolation of the acid by treatment with a suitable acid (e.g.,concentrated hydrochloric acid)(see Example 15).

The preparation of Compound (Ia), as described above, is illustratedschematically below.

(Step B-1)

This step is a step of producing Compound (s)-(I) by optical resolutionof the atropisomer through stirring of the intermediate compound (I) ofthe present invention and an optically active amine in a solvent, andcan be achieved by stirring the above Compound (I) and an opticallyactive amine having a cinchonine skeletal formula in a solvent. Adiastereomeric excess can be determined according to a conventionalmethod.

This method is usually performed in a solvent. The solvent is preferablyan acetate ester, an amide, or a mixed solvent of water and a solventselected therefrom, more preferably a mixed solvent ofN,N-dimethylacetamide, ethyl acetate, and water. According to need,Compound (I) and the optically active amine are dissolved separately,and to the solution of Compound (I), the solution of the opticallyactive amine may be added dropwise.

In this method, the optically active amine having a cinchonine skeletalformula is preferably one compound selected from cinchonine, quinine,cinchonidine, and quinidine represented by the following group ofcompounds:

and more preferably quinine represented by the following formula.

In this method, the amount of the optically active amine having acinchonine skeletal formula used is preferably from 0.5 to 1 equivalentwith respect to Compound (I), more preferably 0.5 equivalents withrespect to Compound (I).

In this method, the reaction mixture may be heated or cooled as needed.A method in which the reaction solution is stirred while heating,followed by cooling to generate crystals is preferred. The heatingtemperature is preferably from room temperature to 100° C., morepreferably from 60° C. to 70° C. The cooling temperature is preferablyfrom 20° C. to 30° C.

An amine salt of Compound (s)-(I) obtained by this step can also beconverted into the free form using an acid. The acid to be used at thistime is not particularly limited as long as it is an acid (an inorganicacid such as hydrochloric acid) usually used for removing an amine salt.

(Step B-2)

This step is a step of obtaining Compound (II) by reacting Compound(s)-(I) and oxalyl chloride in the presence of a base. It is alsopossible to perform Step B-3 successively without isolating andpurifying Compound (II).

This method is usually performed in a solvent. The solvent is preferablyan acetate ester, an ether, or a mixed solvent of these solvents, morepreferably a mixed solvent of 1,2-dimethoxyethane, ethyl acetate, andtetrahydrofuran.

The base is preferably an organic base such as pyridine.

The reaction temperature is from 0° C. to 20° C., preferably from 0° C.to 10° C.

The reaction time is from 1 to 20 hours, preferably 1 to 10 hours.

(Step B-3)

This step is a step of obtaining Compound (III) by reacting Compound(II) and 4-(methylsulfonyl)aniline in the presence of a base.

This method is usually performed in a solvent. The solvent is preferablya nitrile, more preferably a mixed solvent of acetonitrile and water.

The base is preferably an organic base such as pyridine.

The reaction temperature is from 0° C. to 20° C., preferably from 0° C.to 15° C.

The reaction time is from 1 to 2 hours, preferably 1 hour.

It is also possible to perform Step B-4 successively without isolatingand purifying Compound (III), however, a step including a method ofisolating Compound (III) is preferred.

(Step B-4)

This step is a step of obtaining the pyrrole derivative compound (A′) byconverting the hydroxy group of Compound (III) into the free form in thepresence of a base.

This method is usually performed in a solvent. The solvent is preferablyan acetate ester, a nitrile, an ether, or a mixed solvent of water and asolvent selected therefrom, more preferably a mixed solvent of t-butylmethyl ether, acetonitrile, and water.

The base is preferably a metal hydroxide such as potassium hydroxide.

The reaction temperature is from 0° C. to 100° C., preferably from 10°C. to 30° C.

The reaction time is from 0.5 to 20 hours, preferably from 0.5 to 2hours.

After completion of the reaction of the above-mentioned respectivesteps, the target compound can be collected from the reaction mixtureaccording to a conventional method. For example, the reaction mixture isappropriately neutralized, or in the case where insoluble matter ispresent, after the matter is removed by filtration, an organic solventimmiscible with water such as ethyl acetate is added thereto, followedby washing with water or the like. Thereafter, the organic layercontaining the target compound is separated and dried over anhydrousmagnesium sulfate or the like, and then, the solvent is distilled off,whereby the target compound can be obtained.

If necessary, the thus obtained target material can be separated andpurified by a conventional method, for example, by appropriatelycombining recrystallization, reprecipitation, or a method conventionallyused for separation and purification of an organic compound, forexample, a method using a synthetic adsorber such as adsorption columnchromatography or partition column chromatography, a method using ionexchange chromatography, or normal-phase or reverse-phase columnchromatography using silica gel or alkylated silica gel, and performingelution with a suitable eluent.

According to the above-mentioned steps,(−)-1-(2-hydroxyethyl)-5-[4-methoxy-2-(trifluoromethyl)phenyl]-4-methyl-N-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxamidedescribed in WO 2008/126831 can be produced.

Another embodiment of the present invention relates to a medicamentcontaining the crystal of the present invention as an active ingredientand a pharmaceutical composition containing the crystal of the presentinvention.

The medicament containing the crystal of the invention of thisapplication as an active ingredient is preferably provided in the formof a pharmaceutical composition containing the crystal of the presentinvention and one or more pharmaceutically acceptable carriers. Theadministration form of the medicament of the present invention is notparticularly limited, and the medicament can be administered orally orparenterally, but is preferably administered orally.

The pharmaceutical composition of the present invention contains thecrystal of the present invention as Compound (A) at least partially. Inthe pharmaceutical composition, a crystal form other than the crystal ofthe invention of this application may exist as Compound (A). The ratioof the crystal of the invention of this application to be contained inthe pharmaceutical composition with respect to the total amount ofCompound (A) in the pharmaceutical composition may be in the range of0.01% by weight to 99.9% by weight, for example, 0.01% by weight ormore, 0.05% by weight or more, 0.1% by weight or more, 0.5% by weight ormore, 1% by weight or more, 2% by weight or more, 3% by weight or more,4% by weight or more, 5% by weight or more, 10% by weight or more, 20%by weight or more, 30% by weight or more, 40% by weight or more, 50% byweight or more, 60% by weight or more, 70% by weight or more, 80% byweight or more, 90% by weight or more, 95% by weight or more, 96% byweight or more, 97% by weight or more, 98% by weight or more, 99% byweight or more, 99.5% by weight or more, 99.6% by weight or more, 99.7%by weight or more, 99.8% by weight or more, or 99.9% by weight or more.Whether or not the crystal of the invention of this application iscontained in the pharmaceutical composition can be confirmed by aninstrumental analysis method (for example, powder X-ray diffraction,thermal analysis, infrared absorption spectrum, etc.) described in thisdescription.

The pharmaceutical composition of the present invention contains thecrystal of the present invention and a pharmaceutically acceptablecarrier, and can be administered in the form of any of variousinjections through intravenous injection, intramuscular injection,subcutaneous injection, or the like, or through any of various methodssuch as oral administration or transdermal administration. Apharmaceutically acceptable carrier refers to a pharmaceuticallyacceptable material (for example, an excipient, a diluent, an additive,a solvent, etc.) which is involved in transport of the crystal of thepresent invention from a given body part or organ to another body partor organ.

As a method for preparing a formulation, for example, an appropriateformulation (for example, an oral preparation or an injection) isselected according to the administration method, and can be prepared bya conventionally used preparation method for various formulations.Examples of oral preparations can include a tablet, a powder, a granule,a capsule, a pill, a troche, a solution, a syrup, an elixir, anemulsion, and an oily or aqueous suspension. In the case of aninjection, a stabilizer, a preservative, a solubilizing agent, or thelike can also be used in the formulation. It is also possible to form asolid preparation as a formulation to be prepared before use by placinga solution which may contain such a pharmaceutical aid or the like in acontainer, followed by lyophilization or the like. In addition, a singledosage may be packed in one container, or multiple dosages may be packedin one container.

Examples of solid preparations include a tablet, a powder, a granule, acapsule, a pill, and a troche. These solid preparations may contain apharmaceutically acceptable additive along with the crystal of thepresent invention. Examples of additives include a filler, an expander,a binder, a disintegrant, a solubilization enhancer, a wetting agent,and a lubricant, and the solid preparation can be prepared by selectingan additive therefrom according to need and mixing.

Examples of liquid preparations include a solution, a syrup, an elixir,an emulsion, and a suspension. These liquid preparations may contain apharmaceutically acceptable additive along with the crystal of thepresent invention. Examples of additives include a suspending agent andan emulsifying agent, and the liquid preparation can be prepared byselecting an additive therefrom according to need and mixing.

For example, in the case of a tablet, in the entire pharmaceuticalcomposition, the content of a binder is generally from 1 to 10 parts byweight (preferably from 2 to 5 parts by weight), the content of adisintegrant is generally from 1 to 40 parts by weight (preferably from5 to 30 parts by weight), the content of a lubricant is generally from0.1 to 10 parts by weight (preferably from 0.5 to 3 parts by weight),and the content of a fluidizing agent is generally from 0.1 to 10 partsby weight (preferably from 0.5 to 5 parts by weight).

The pharmaceutical composition of the present invention can beadministered to a warm-blooded animal (particularly a human being). Thedose of Compound (A) or a pharmacologically acceptable salt thereofwhich is an active ingredient varies depending on the various conditionssuch as symptoms, age, and body weight of a patient, however, in thecase of, for example, oral administration, it can be administered to ahuman being at a dose of 0.1 mg/body to 20 mg/body (preferably 0.5mg/body to 10 mg/body) one to three times per day depending on thesymptoms.

Advantageous Effects of Invention

According to the present invention, a method for producing a pyrrolederivative compound (A′) having mineralocorticoid receptor antagonisticactivity and a production intermediate compound thereof are provided.Further, a crystal of(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,a method for producing the same, and a production intermediate compoundthereof are provided. The crystal of the present invention has excellentstability and is useful as a medicament such as an antihypertensivedrug.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of the crystal obtainedin Example 8. In the drawing, the ordinate represents diffractionintensity in units of count/sec (cps), and the abscissa representsvalues of diffraction angle 2θ.

FIG. 2 shows a DSC curve of a crystal (Crystal A) obtained in Example 8.In the drawing, the ordinate represents heat flow (mW), and the abscissarepresents temperature (° C.).

DESCRIPTION OF EMBODIMENTS

Hereinafter, the present invention will be described in more detail byshowing Examples of the present invention and the like, however, thescope of the present invention is not limited thereto.

EXAMPLES Example 1 2-Bromo-1-[2-(trifluoromethyl)phenyl]propan-1-one

To 1-[2-(trifluoromethyl)phenyl]propan-1-one (75 g (370 mmol)), t-butylmethyl ether (750 mL) and bromine (1.18 g (7.4 mmol)) were added. Theresulting mixture was stirred at 15 to 30° C. for about 30 minutes, andafter it was confirmed that the color of bromine disappeared, themixture was cooled to 0 to 5° C. While maintaining the temperature at 0to 10° C., bromine (59.13 g (370 mmol)) was added thereto, and theresulting mixture was stirred. After the mixture was stirred for about2.5 hours, a 10 w/v % aqueous potassium carbonate solution (300 mL) wasadded thereto while maintaining the temperature at 0 to 25° C., andsodium sulfite (7.5 g) was further added thereto, followed by heating to20 to 30° C. This solution was subjected to liquid separation, and tothe obtained organic layer, water (225 mL) was added to wash the organiclayer. Thereafter, the organic layer was concentrated under reducedpressure, whereby a t-butyl methyl ether solution (225 mL) of the titlecompound was obtained.

¹H NMR (400 MHz, CDCl₃) δ: 1.91 (3H, d, J=4.0 Hz), 4.97 (1H, q, J=6.7Hz), 7.60-7.74 (4H, m)

Example 2 Ethyl2-cyano-3-methyl-4-oxo-4-[2-(trifluoromethyl)phenyl]butanoate

To the 2-bromo-1-[2-(trifluoromethyl)phenyl]propan-1-one/t-butyl methylether solution (220 mL) obtained in Example 1, dimethylacetamide (367mL), cyanoethyl acetate (53.39 g (472 mmol)), and potassium carbonate(60.26 g (436 mmol)) were sequentially added, and the resulting mixturewas heated to 45 to 55° C. and stirred. After the mixture was stirredfor about 2 hours, the mixture was cooled to 20 to 30° C., and thenwater (734 mL) and toluene (367 mL) were added thereto to effectextraction. Then, water (513 mL) was added to the resulting organiclayer to wash the organic layer (washing was performed twice).Thereafter, the obtained organic layer was concentrated under reducedpressure, whereby a toluene solution (220 mL) of the title compound wasobtained.

¹H NMR (400 MHz, CDCl₃) δ: 1.33-1.38 (6H, m), 3.80-3.93 (2H, m),4.28-4.33 (2H, m), 7.58-7.79 (4H, m).

Example 3 Ethyl2-chloro-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

To the toluene solution (217 mL) of ethyl2-cyano-3-methyl-4-oxo-4-[2-(trifluoromethyl)phenyl]butanoate obtainedby the production method of Example 2, ethyl acetate (362 mL) andthionyl chloride (42.59 g (358 mmol)) were added at 20 to 30° C.,followed by cooling to −10 to 5° C. Then, hydrogen chloride gas (52.21 g(1432 mmol)) was blown into the mixture, and concentrated sulfuric acid(17.83 g (179 mmol)) was further added thereto, and the resultingmixture was heated and stirred at 15 to 30° C. After the mixture wasstirred for about 20 hours, ethyl acetate (1086 mL) was added thereto,followed by heating to 30 to 40° C., and water (362 mL) was addedthereto, and then, the resulting mixture was subjected to liquidseparation. To the organic layer obtained by liquid separation, water(362 mL) was added, followed by liquid separation, and then, a 5 w/v %aqueous sodium hydrogen carbonate solution (362 mL) was added thereto,followed by liquid separation.

Subsequently, the organic layer was concentrated under reduced pressure,and toluene (579 mL) was further added thereto, followed byconcentration under reduced pressure, and then, toluene (72 mL) wasadded thereto, and the mixture was cooled to 0 to 5° C. After themixture was stirred for about 2 hours, the deposited crystal wasfiltered and washed with toluene (217 mL) cooled to 0 to 5° C. Theobtained wet crystal product was dried under reduced pressure at 40° C.,whereby the title compound was obtained (97.55 g, yield: 82.1%).

¹H NMR (400 MHz, CDCl₃) δ: 1.38 (3H, t, J=7.1 Hz), 2.11 (3H, s), 4.32(2H, q, J=7.1 Hz), 7.39 (1H, d, J=7.3 Hz), 7.50-7.62 (2H, m), 7.77 (1H,d, J=8.0 Hz), 8.31 (1H, br).

Example 4 Ethyl4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

To ethyl2-chloro-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate(97.32 g (293 mmol)) obtained by the production method of Example 3,ethanol (662 mL), tetrahydrofuran (117 mL), water (49 mL), sodiumformate (25.91 g (381 mmol)), and a 5% palladium-carbon catalyst (watercontent: 52.1%, 10.16 g) were added at room temperature, and theresulting mixture was heated to 55 to 65° C. and stirred. After themixture was stirred for about 1 hour, the mixture was cooled to 40° C.or lower, and tetrahydrofuran (97 mL) and a filter aid (KC Flock, NipponPaper Industries) (4.87 g) were added thereto. Then, the catalyst wasfiltered, and the residue was washed with ethanol (389 mL). The filtrateand the ethanol solution used for washing were combined, and thecombined solution was concentrated under reduced pressure. Thereafter,water (778 mL) was added thereto and the mixture was stirred at 20 to30° C. for 0.5 hours or more. The deposited crystal was filtered andwashed with a mixed solution of ethanol/water=7/8 (292 mL). The thusobtained wet crystal product was dried under reduced pressure at 40° C.,whereby the title compound was obtained (86.23 g, yield: 98.9%).

¹H NMR (400 MHz, CDCl₃) δ: 1.35 (3H, t, J=7.1 Hz), 2.18 (3H, s), 4.29(2H, m), 7.40-7.61 (4H, m), 7.77 (1H, d, J=7.9 Hz), 8.39 (1H, br)

Example 5 Ethyl(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

To ethyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate(65.15 g (219 mmol)) obtained by the production method of Example 4,N,N-dimethylacetamide (261 mL), ethylene carbonate (28.95 g (328.7mmol)), and 4-dimethylaminopyridine (2.68 g (21.9 mmol)) weresequentially added at room temperature, and the resulting mixture washeated to 105 to 120° C. and stirred. After the mixture was stirred forabout 10 hours, the mixture was cooled to 20 to 30° C., and toluene(1303 mL) and water (326 mL) were added thereto, and the organic layerwas extracted. Then, water (326 mL) was added to the organic layer towash the organic layer (washing was performed three times). The obtainedorganic layer was concentrated under reduced pressure, and ethanol (652mL) was added thereto, and the resulting mixture was furtherconcentrated under reduced pressure. Thereafter, ethanol (130 mL) wasadded thereto, whereby an ethanol solution of the title compound (326mL) was obtained.

¹H NMR (400 MHz, CDCl₃) δ: 1.35 (3H, t, J=7.1 Hz), 1.84 (1H, broadsinglet), 2.00 (3H, s), 3.63-3.77 (4H, m), 4.27 (2H, m), 7.35-7.79 (5H,m)

Example 6(RS)-1-(2-Hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid

To the solution of ethyl(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate/ethanolsolution (321 mL) obtained by the production method of Example 5, water(128.6 mL) and sodium hydroxide (21.4 g (519 mmol)) were added at roomtemperature, and the resulting mixture was heated and stirred at 65 to78° C. After the mixture was stirred for about 6 hours, the mixture wascooled to 20 to 30° C., and water (193 mL) was added thereto. Then, thepH of the resulting mixture was adjusted to 5.5 to 6.5 using 6 Nhydrochloric acid while maintaining the temperature at 20 to 30° C. Tothe mixture whose pH was adjusted,(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid (6.4 mg) was added as a seed crystal, and water (193 mL) wasfurther added. Then, the mixture was cooled to 0 to 5° C., and again,the pH of the mixture was adjusted to 3 to 4 using concentratedhydrochloric acid, and the mixture was stirred for about 1 hour.Thereafter, the deposited crystal was filtered and washed with a 20%aqueous ethanol solution (93 mL) cooled to 0 to 5° C. The thus obtainedwet crystal product was dried under reduced pressure at 40° C., wherebythe title compound was obtained (64.32 g, yield: 95.0%).

¹H NMR (400 MHz, DMSO-d₆) δ: 1.87 (3H, s), 3.38-3.68 (4H, m), 7.43-7.89(5H, m)

Example 7(S)-1-(2-Hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid quinine salt (7-1)(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid quinine salt

To(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid (50.00 g (160 mmol)) obtained by the production method of Example6, N,N-dimethylacetamide (25 mL) and ethyl acetate (85 mL) were added atroom temperature and dissolved therein. (Solution 1)

To quinine (31.05 g (96 mmol)), N,N-dimethylacetamide (25 mL), ethylacetate (350 mL), and water (15 mL) were added, and the resultingmixture was heated to 65 to 70° C., and then, Solution 1 was addeddropwise thereto. After the mixture was stirred at 65 to 70° C. forabout 1 hour, the mixture was gradually cooled to 0 to 5° C. (coolingrate as a guide: about 0.3° C./min) and stirred for about 0.5 hours atthat temperature. The resulting crystal was filtered and washed withethyl acetate (100 mL) cooled to 5° C. or lower, and the obtained wetcrystal product was dried under reduced pressure at 40° C., whereby thetitle compound (43.66 g) was obtained (yield: 42.9%). The diastereomericexcess of the obtained salt was 98.3% de.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.30-2.20 (10H, m), 2.41-2.49 (2H, m),2.85-3.49 (6H, m), 3.65-3.66 (1H, m), 3.88 (3H, s), 4.82 (1H, broadsinglet), 4.92-5.00 (2H, m), 5.23-5.25 (1H, m), 5.60 (1H, br), 5.80-6.00(1H, m), 7.36-7.92 (9H, m), 8.67 (1H, d, J=4.6 Hz)

(7-2) HPLC determination for diastereomeric excess (% de) of(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylis acid quinine salt

About 10 mg of the title compound was collected and diluted with a 50v/v % aqueous acetonitrile solution to 10 mL, whereby a sample solutionwas prepared.

Column: DAICEL CHIRALPAK IC-3 (4.6 mm I.D.×250 mm, 3 μm)

Mobile phase A: a 0.02 mol/L phosphate buffer solution (pH 3)

Mobile phase B: acetonitrile

Supply of mobile phase: The mixing ratio of the mobile phase A to themobile phase B is shown in the following Table 1.

TABLE 1 Time Mobile phase Mobile phase (min) A (vol %) B (vol %)  0-13100 0 13-18 100 → 40 0 → 60 18-20 100 0 Detection: UV 237 nm Flow rate:about 0.8 mL/min Column temperature: constant temperature at around 30°C. Measurement time: about 20 min Injection volume: 5 μL

The diastereomeric excess (% de) was calculated according to thefollowing formula using the peak area ratios of the title compound(retention time: about 12 min) and the R form (retention time: about 13min).% de={[(the peak area ratio of the title compound (S form))−(the peakarea ratio of the R form)]÷[(the peak area ratio of the title compound(S form))+(the peak area ratio of the R form)]}×100

Example 8(S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide(Compound (A)) (8-1)(S)-1-(2-Hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid

To(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid (8α,9R)-6′-methoxycinchonan-9-ol (40.00 g (63 mmol)) obtained bythe production method of Example 7, ethyl acetate (400 mL) and a 2 Naqueous hydrochloric acid solution (100 mL) were added, and theresulting mixture was stirred at room temperature, followed by liquidseparation. The obtained organic layer was concentrated under reducedpressure (120 mL), ethyl acetate (200 mL) was added thereto, and theresulting mixture was further concentrated under reduced pressure,whereby a solution containing the title compound (120 mL) was obtained.

(8-2)2-((S)-3-Methyl-4-{[4-(methylsulfonyl)phenyl]carbamoyl}-2-[2-(trifluoromethyl)phenyl]-1H-pyrrol-1-yl)ethylN-{[4-(methylsulfonyl)phenyl]amino}oxamate

Ethyl acetate (240 mL), tetrahydrofuran (80 mL), and oxalyl chloride(20.72 g (163 mmol)) were mixed, and the resulting mixture was cooled to10 to 15° C. Subsequently, the solution obtained in Example (8-1) wasadded thereto while maintaining the temperature at 10 to 15° C., and theresulting mixture was heated to 15 to 20° C. and stirred for about 1hour. After stirring, acetonitrile (120 mL) and pyridine (2.46 g (31mmol)) were added thereto, and the reaction solution was concentratedunder reduced pressure (120 mL), and acetonitrile (200 mL) was addedthereto, and the resulting mixture was further concentrated underreduced pressure (120 mL).

After completion of concentration under reduced pressure, acetonitrile(200 mL) was added thereto, and the resulting mixture was cooled to 10to 15° C. (Reaction Solution 1).

After acetonitrile (240 mL), pyridine (12.39 g (157 mmol)), and4-(methylsulfonyl)aniline (26.85 g (157 mmol)) were sequentially added,Reaction Solution 1 was added thereto while maintaining the temperatureat 10 to 15° C., and the resulting mixture was heated to 20 to 25° C.and stirred for about 1 hour.

To the thus obtained reaction solution, acetonitrile (40 mL), a 2 Naqueous hydrochloric acid solution (120 mL), and sodium chloride (10.0g) were added, and the resulting mixture was stirred, followed by liquidseparation. Again, to the organic layer, a 2 N aqueous hydrochloric acidsolution (120 mL) and sodium chloride (10.0 g) were added, and theresulting mixture was stirred, followed by liquid separation. Theobtained organic layer was filtered and concentrated under reducedpressure (400 mL). To the concentrated liquid, water (360 mL) was added,and stirred for about 1 hour. Then, the resulting crystal was filteredand washed with a 50 v/v % aqueous acetonitrile solution (120 mL),whereby a wet product of the title compound (undried product, 62.02 g)was obtained.

¹H NMR (500 MHz, DMSO-d₆) δ: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H),3.81 (t, 1H), 4.12 (t, 1H), 4.45 (t, 2H, J=5.81 Hz), 7.62 (t, 1H, J=4.39Hz), 7.74 (t, 2H, J=3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J=6.94, 2.13Hz), 7.97 (dd, 2H, J=6.80, 1.98 Hz), 8.02 (dd, 2H), 10.03 (s, 1H), 11.19(s, 1H)

(8-3)(S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide(Compound (A))

To the crystal of the wet product obtained in (8-2), t-butyl methylether (200 mL), acetonitrile (40 mL), a 48 w/w aqueous potassiumhydroxide solution (16 g), and water (200 mL) were added, and theresulting mixture was stirred at 25 to 35° C. for about 2 hours. Afterstirring, liquid separation was performed, and the obtained organiclayer was concentrated under reduced pressure (120 mL), and ethanol (240mL) was added thereto, and the resulting mixture was furtherconcentrated under reduced pressure (120 mL). After completion ofconcentration under reduced pressure, ethanol (36 mL) and water (12 mL)were added thereto, and the resulting mixture was heated to 35 to 45°C., and then, water (280 mL) was added dropwise thereto whilemaintaining the temperature at 35 to 45° C. to deposit a crystal. Thecrystallization solution was cooled to room temperature, and the crystalwas filtered. Then, the crystal was washed with a 30 v/v % aqueousethanol solution (80 mL) and dried under reduced pressure at 40° C.,whereby the title compound was obtained in the form of a crystal (26.26g, yield: 89.7%). The amount of enantiomer of the obtained crystal was0.3%.

¹H NMR (400 MHz, CDCl₃) δ: 1.74 (1H, broad singlet), 2.08 (3H, s), 3.04(3H, s), 3.63-3.80 (4H, m), 7.36 (1H, d, J=7.2 Hz), 7.48 (1H, s),7.58-7.67 (2H, m), 7.77-7.90 (6H, m)

(8-4) HPLC determination method for amount (%) of enantiomer of(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

About 10 mg of the title compound was collected and diluted with a 50v/v % aqueous acetonitrile solution to 10 mL, whereby a sample solutionwas prepared.

Column: DAICEL CHIRALPAK OJ-RH (4.6 mm I.D.×150 mm, 5 μm)

Mobile phase A: acetonitrile/water=9/16

Mobile phase B: acetonitrile

Supply of mobile phase: The mixing ratio of the mobile phase A to themobile phase B is shown in the following Table 2.

TABLE 2 Time Mobile phase Mobile phase (min) A (vol %) B (vol %)  0-10100 0 10-20 100 → 30 0 → 70 20-30 100 0 Detection: UV 287 nm Flow rate:about 0.8 mL/min Column temperature: constant temperature at around 30°C. Measurement time: about 30 min Injection volume: 5 μL

The amount of enantiomer was calculated according to the followingformula using the peak areas of the title compound (retention time:about 9.2 min) and the enantiomer (retention time: about 8.2 min).Amount of enantiomer (%)=(the peak area of the enantiomer÷the peak areaof the title compound)×100

(8-5) X-ray diffractometry of(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

X-ray diffractometry was performed for the crystal of the title compoundobtained in (8-3) by filling the sample in a glass sample holder usingan X-ray diffractometer RINT 2200V manufactured by Rigaku Corporationunder the following conditions. The diffraction pattern of the powderX-ray diffraction (CuKα, λ=1.54 Å) of the obtained crystal is shown inFIG. 1, and the peaks having a relative intensity of 5 or more when themaximum peak intensity in FIG. 1 was taken as 100 are shown in Table 3.

TABLE 3 Peak Relative No. 2θ d value intensity 1 6.80 12.99 52 2 9.908.93 5 3 10.82 8.17 7 4 11.18 7.91 5 5 12.32 7.18 22 6 12.58 7.03 5 713.60 6.51 18 8 14.10 6.28 12 9 14.46 6.12 46 10 14.90 5.94 6 11 15.285.798 9 12 15.76 5.62 6 13 16.30 5.43 44 14 17.06 5.19 55 15 17.36 5.108 16 17.62 5.03 8 17 17.82 4.97 8 18 18.42 4.81 18 19 19.24 4.61 100 2019.86 4.47 37 21 20.36 4.36 35 22 20.84 4.26 18 23 21.84 4.07 50 2422.52 3.94 24 25 22.80 3.90 56 26 23.20 3.83 27 27 23.50 3.78 14 2824.60 3.62 66 29 25.48 3.499 56 30 25.98 3.43 11 31 26.96 3.30 21 3227.52 3.24 16 33 28.10 3.17 9 34 28.32 3.15 12 35 28.66 3.11 6 36 29.263.05 30 37 30.56 2.92 10 38 30.94 2.89 11 39 31.80 2.81 19 40 32.08 2.7917 41 32.46 2.76 8 42 32.74 2.73 9 43 33.96 2.64 9 44 34.54 2.59 6 4535.00 2.56 5 46 35.50 2.53 14 47 35.82 2.50 23 48 36.44 2.46 11 49 36.982.43 10 50 37.44 2.40 6 51 38.06 2.36 6 52 38.92 2.31 12 53 39.54 2.28 554 40.34 2.23 16 55 40.98 2.20 5 56 41.36 2.18 21 57 41.96 2.15 7 5842.18 2.14 9 59 43.64 2.07 10 60 44.42 2.04 11<Analysis Conditions>X ray: Cu-Kα1/40 kV/40 mAGoniometer: Ultima+horizontal goniometer I2θ scanning range: 2 to 45°

(8-6) Differential scanning calorimetry of(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

About 5 mg of a test compound was weighed and placed on an aluminum panfor measurement, and calorimetry was performed in a temperature rangefrom room temperature to 250° C. at a heating rate of 5° C./min in astate where the pan was opened using a differential scanning calorimeterDSC 3100 manufactured by Mac Science Corporation. The DSC curve obtainedby the differential scanning calorimetry is shown in FIG. 2.

Example 9 Production of(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid by optical resolution of racemic compound (9-1) Effect of VariousAmines or Various Solvents

Various solvents were added to(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid (100 mg (319.2 mmol)) and various amines (0.5 equivalents) at roomtemperature. The resulting mixture was stirred at room temperature forabout 1 hour or stirred for about 1 hour while heating, and thereaftergradually cooled to 20 to 30° C., and then, the mixture was stirred forabout 0.5 hours at that temperature. Then, the resulting crystal wasfiltered, and the obtained wet crystal product was dried under reducedpressure, whereby the crystal was obtained. Further, the diastereomericexcess of the obtained salt was determined.

(9-2) HPLC Determination Method for Diastereomeric Excess of TitleCompound

About 10 mg of the title compound was collected and diluted with amobile phase to 20 mL, whereby a sample solution was prepared.

Column: DAICEL CHIRALCEL OD-RH (4.6 mm I.D.×150 mm, 5 μm)

Mobile phase: a 0.1 v/v % aqueous acetic acid solution (prepared bymixing 1 mL of acetic acid in 1000 mL of distilledwater):acetonitrile=75:25

Detection: UV 220 nm

Flow rate: about 1.0 mL/min

Column temperature: constant temperature at around 40° C.

Measurement time: about 25 min

Injection volume: 5 μL

The diastereomeric excess was calculated according to the followingformula using the peak area ratios of the title compound (retentiontime: about 14.5 min) and the R form (retention time: about 15.5 min).% de={[(the peak area ratio of the title compound (S form))−(the peakarea ratio of the R form)]÷[(the peak area ratio of the title compound(S form))+(the peak area ratio of the R form)]}×100

When various examinations were performed for the systems in which acrystal (a diastereomer salt) was obtained using the above-mentionedamines, quinine and quinidine gave a diastereomer salt having a desiredabsolute configuration (S form), and cinchonidine gave a diastereomersalt having an opposite absolute configuration (R form). The mainresults are shown in Table 4.

Hereinafter, in the table, EtOAc represents ethyl acetate, CH₃CNrepresents acetonitrile, and DME represents dimethoxyethane.

TABLE 4 Solvent Temper- (amount ature % Yield Amine of solvent) ° C. de% 1 Quinine EtOAc (0.2 ml) Filtration 69 (S form) 43.7 at room temper-ature 2 EtOAc (0.3 ml) 50 → 20 90 (S form) 42.5 3 CH₃CN (0.3 ml) 50 → 2079 (S form) 45.2 4 Acetone (0.3 ml) 50 → 20 95 (S form) 43.5 5 DME (0.3ml) 50 → 20 91 (S form) 39.5 6 Cinchonidine EtOAc (0.3 ml) 50 → 20 88 (Rform) 33.4 7 Quinidine CH₃CN-water 50 → 20 58 (S form) 44.5 (about 0.3ml) 8 acetone-water 50 → 20 60 (S form) 44.0 (about 0.3 ml) 9 DME-water50 → 20 59 (S form) 48.9 (about 0.3 ml)

When optical resolution was performed in the same manner using(R)-(−)-α-phenylglycitol, (S)-(−)-N,N-dimethyl-1-phenyl-ethylmine,L-lysine, and the like, the diastereomeric excess was 5% de or less.

Next, the number of equivalents of amine was examined for the purpose ofimproving the amount of diastereomer. The results of the examination areshown in Table 5.

TABLE 5 Number of Temperature Entry Amine equivalents Solvent ° C. % deYield % 1 Quinine 0.45 Acetone 50 → 20 94 39.4 (0.3 ml) (S form) 2 0.5095 43.5 (S form) 3 0.55 93 43.5 (S form) 4 Quinidine 0.45 EtOAc 50 → 2092 32.1 (0.3 ml) (R form) 5 0.50 88 33.4 (R form)

Based on the above results, quinine gave a diastereomer having a desiredabsolute configuration (S form), and cinchonidine gave a diastereomersalt having an opposite absolute configuration (R form) with high purityin medium to high yield.

Example 10 Production of(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid quinine salt by racemization of(R)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid (10-1) Production of(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid quinine salt by racemization of(R)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid

The filter washing liquid (583.63 g, content of(R)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid and(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylis acid: 22.23 g) obtained by the optical resolution method of(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid described in (Example 7) was concentrated under reduced pressure(75.73 g). The obtained concentrated liquid was heated to 140 to 150° C.and stirred for about 5 hours, and thereafter cooled and concentratedunder reduced pressure (Reaction Solution 1, 40 mL).

After ethyl acetate (220 mL), water (7.3 mL), and quinine (19.18 g (59mmol)) were mixed at room temperature, Reaction Solution 1 was addedthereto at the same temperature. The resulting mixture was heated toabout 65° C., and thereafter gradually cooled to 0 to 5° C. (coolingrate as a guide: about 0.3° C./min) and stirred for about 1 hour at thattemperature. The resulting crystal was filtered and washed with ethylacetate (40 mL) cooled to 0 to 5° C., and the obtained wet crystalproduct was dried under reduced pressure at 40° C., whereby(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid quinine salt (19.59 g) was obtained (yield: 43.3%). Thediastereomeric excess of the obtained salt was determined by using themethod of (Example 7-2) and found to be 94.8% de.

(10-2-1) Racemization of (R)-1-(2-hydroxyethyl)-4-methyl-5[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid

The filter washing liquid obtained by the optical resolution method of(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid described in (Example 7) was concentrated under reduced pressure.To the residue (15.46 g) (a foam shape, R form, 84.6% ee, Net 14.38 g),N,N-dimethylformamide (77 mL) was added, and the resulting mixture washeated to 140 to 145° C. and stirred for about 6 hours. Then, themixture was cooled to room temperature, and water (77 mL) and toluene(464 mL) were added thereto to effect extraction, and the obtainedorganic layer was washed three times with water (77 mL). The washedorganic layer was concentrated under reduced pressure (155 mL) andcooled to 0 to 5° C. and stirred for about 1 hour at that temperature.The resulting crystal was filtered and washed with toluene (31 mL)cooled to 0 to 5° C. The obtained wet crystal product was dried underreduced pressure at 40° C., whereby(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid was obtained (10.70 g, content: 95.2% (Net 10.19 g), 0.5% ee,yield: 70.9%). The content was determined by using the method describedin (10-2-2).

By using the obtained(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid as a starting material, and also using the method described inExample 7,(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid quinine salt can be produced.

(10-2-2) HPLC Determination Method for Content

About 25 mg of(R)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid was collected and diluted with a mobile phase to 50 mL, whereby astandard solution or a sample solution was prepared.

Column: L-column C8 (4.6 mm I.D.×250 mm, 5 μm) available from Chemicals

Evaluation and Research Institute

Mobile Phase:

Solution A: acetonitrile:a 5 mM aqueous disodium hydrogen phosphatesolution=20:80

Solution B: acetonitrile:water=80:20

The gradient composition is shown in Table 6.

TABLE 6 Time (min) 0-5 5-15 15-30 Solution A:Solution B 85:15 85:15 →0:100 0:100 Detection: UV 254 nm Flow rate: about 1.0 mL/min Columntemperature: constant temperature at around 40° C. Measurement time:about 30 min Injection volume: 5 μL

The content was calculated according to the following formula using thepeak area of the title compound (retention time: about 6.5 min)(absolute calibration curve method).Content (%)=F×(Ws÷Wt)×(Qt÷Qs)Ws: weight of reference standard (mg), Wt: weight of unknown sample(mg), Qs: peak area of standard solution, Qt: peak area of samplesolution, F: content of reference standard (%)

Example 11(R)-1-(2-Hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid cinchonidine salt

To cinchonidine (46.98 g (159.6 mmol)), ethyl acetate (1400 mL) wasadded, and while heating and stirring the resulting mixture under reflux(about 78° C.),(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid (50.00 g (159.6 mmol)) was added thereto. The resulting mixture wasstirred for about 1 hour, and then gradually cooled to 20 to 30° C., andfurther stirred for about 1 hour at that temperature. The depositedcrystal was filtered and washed with ethyl acetate (250 mL). Theobtained wet crystal product was dried under reduced pressure at 40° C.,whereby a crude product of the title compound (52.73 g) was obtained(yield: 54.4%). The diastereomeric excess of the obtained salt was 71.9%de.

To the obtained crude product (50.00 g), ethanol (75 mL) and ethylacetate (100 mL) were added, and the resulting mixture was heated andstirred under reflux (about 78° C.). After the mixture was stirred forabout 1 hour, ethyl acetate (825 mL) was added thereto, and theresulting mixture was stirred under reflux again for about 0.5 hours.Thereafter, the mixture was cooled to 0 to 5° C. and stirred for about 1hour at that temperature. The resulting crystal was filtered and washedwith ethyl acetate (200 mL) cooled to 0 to 5° C. The obtained wetcrystal product was dried under reduced pressure at 40° C., whereby thetitle compound was obtained (34.21 g, recovery rate: 68.4%, yield:37.2%). The diastereomeric excess of the obtained salt was 98.7% de.

¹H NMR (400 MHz, CDCl₃) δ: 1.27-1.67 (m, 2H), 1.75-2.04 (m, 4H),2.13-2.33 (m, 1H), 2.52-2.94 (m, 2H), 3.14-3.23 (m, 2H), 3.46-4.12 (m,2H), 4.76-5.10 (m, 2H), 5.58-5.90 (m, 2H), 6.10-6.95 (m, 2H), 7.00-8.25(m, 7H), 8.55-9.01 (m, 1H). MS (ESI): 313, 294

Example 12 Production method (2) for(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide(Compound (A)) (12-1)(S)-1-(2-Hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid

To(S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid (8α,9R)-6′-methoxycinchonan-9-ol (10.00 g (16 mmol)) obtained bythe production method of Example 7, t-butyl methyl ether (90 mL), water(10 mL), and a 36 w/w % aqueous hydrochloric acid solution (5 mL) wereadded, and the resulting mixture was stirred at room temperature,followed by liquid separation. The obtained organic layer wasconcentrated under reduced pressure (30 mL), and ethyl acetate (50 mL)was added thereto, and the resulting mixture was further concentratedunder reduced pressure, whereby a solution containing the title compound(30 mL) was obtained.

(12-2)2-((S)-3-Methyl-4-{[4-(methylsulfonyl)phenyl]carbamoyl}-2-[2-(trifluoromethyl)phenyl]-1H-pyrrol-1-yl)ethylN-{[4-(methylsulfonyl)phenyl]amino}oxamate

Ethyl acetate (50 mL), tetrahydrofuran (20 mL), and oxalyl chloride(5.18 g (41 mmol)) were mixed, and the resulting mixture was cooled to 0to 5° C. Then, the solution obtained in Example (12-1) was added theretowhile maintaining the temperature at 0 to 5° C., and the resultingmixture was stirred at 0 to 10° C. for 6 hours. After stirring,acetonitrile (30 mL) and pyridine (0.62 g (8 mmol)) were added thereto,and the reaction solution was concentrated under reduced pressure (30mL), and acetonitrile (50 mL) was added thereto, and the resultingmixture was further concentrated under reduced pressure (30 mL).

After completion of concentration under reduced pressure, acetonitrile(10 mL) and oxalyl chloride (0.10 g (1 mmol)) were added thereto, andthe resulting mixture was cooled to 0 to 5° C. (Reaction Solution 1).

After acetonitrile (30 mL), pyridine (3.15 g (40 mmol)), and4-(methylsulfonyl)aniline (6.71 g (39 mmol)) were sequentially added,Reaction Solution 1 was added thereto while maintaining the temperatureat 10 to 15° C., and the resulting mixture was heated to 20 to 25° C.and stirred for about 1 hour.

Insoluble matter was filtered from the obtained reaction solution andwashed with acetonitrile (10 mL), and then water (15 mL) was addedthereto, and the resulting mixture was stirred for about 2 hours. Then,water (75 mL) was added dropwise thereto over about 1 hour. After theresulting suspension was stirred for about 1 hour, the crystal wasfiltered and washed with a 50 v/v % aqueous acetonitrile solution (20mL), whereby a wet product of the title compound (undried product, 15.78g) was obtained

¹H NMR (500 MHz, DMSO-d₆) δ: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H),3.81 (t, 1H), 4.12 (t, 1H), 4.45 (t, 2H, J=5.81 Hz), 7.62 (t, 1H, J=4.39Hz), 7.74 (t, 2H, J=3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J=6.94, 2.13Hz), 7.97 (dd, 2H, J=6.80, 1.98 Hz), 8.02 (dd, 2H), 10.03 (s, 1H), 11.19(s, 1H)

(12-3)(S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide(Compound (A))

To the crystal of the wet product obtained in (12-2), t-butyl methylether (50 mL), acetonitrile (10 mL), a 48 w/w aqueous potassiumhydroxide solution (4 g), and water (50 mL) were added, and theresulting mixture was stirred at 15 to 25° C. for about 2 hours. Afterstirring, liquid separation was performed, and the obtained organiclayer was concentrated under reduced pressure (30 mL), and ethanol (60mL) was added thereto, and the resulting mixture was furtherconcentrated under reduced pressure (30 mL). After completion ofconcentration under reduced pressure, ethanol (14 mL) and water (20 mL)were added thereto, and then, a seed crystal was added thereto todeposit a crystal. After water (50 mL) was added dropwise thereto overabout 1 hour, the resulting mixture was stirred for about 1 hour, andthe resulting crystal was filtered. Thereafter, the crystal was washedwith a 30 v/v % aqueous ethanol solution (10 mL) and dried under reducedpressure at 40° C., whereby the title compound was obtained in the formof a crystal (6.36 g, yield: 87.0%). The amount of enantiomer of theobtained crystal was 0.05%. The amount of enantiomer was determined bythe method described in (Example 8-4).

¹H NMR (400 MHz, CDCl₃) δ: 1.74 (1H, broad singlet), 2.08 (3H, s), 3.04(3H, s), 3.63-3.80 (4H, m), 7.36 (1H, d, J=7.2 Hz), 7.48 (1H, s),7.58-7.67 (2H, m), 7.77-7.90 (6H, m)

Example 13 Ethyl(RS)-2-chloro-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

To ethyl2-chloro-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate(40.01 g (121 mmol)) obtained by the production method of Example 3,ethylene carbonate (13.82 g (157 mmol)), 4-dimethylaminopyridine (1.50 g(12.2 mmol)), and N,N-dimethylacetamide (80 mL) were sequentially addedat room temperature, and the resulting mixture was heated to 105 to 120°C. and stirred. After about 3 hours, the mixture was cooled to 10° C. to25° C., and toluene (600 mL), water (180 mL), and concentratedhydrochloric acid (60 mL) were added thereto, and the organic layer wasextracted. Then, to the organic layer, water (200 mL) was added to washthe organic layer (washing was performed twice). The obtained organiclayer was concentrated under reduced pressure, and ethanol (400 mL) wasadded thereto, and the resulting mixture was concentrated under reducedpressure, whereby an ethanol solution of the title compound (about 120mL) was obtained.

1H-NMR (500 MHz, CDCl3) δ: 1.36 (dt, 4H, J=11.99, 5.08 Hz), 1.55 (s,1H), 1.93 (s, 3H), 3.66 (dtt, 3H, J=40.62, 12.53, 4.65 Hz), 3.95-4.00(m, 1H), 4.30 (q, 2H, J=7.19 Hz), 7.36 (t, 1H, J=3.72 Hz), 7.59 (ddd,2H, J=20.65, 9.24, 5.27 Hz), 7.78 (d, 1H, J=7.69 Hz)

Example 14 Ethyl(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

To the ethyl(RS)-2-chloro-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate/ethanolsolution (about 120 mL) obtained by the production method of Example 13,ethanol (160 mL), sodium formate (10.68 g (157 mmol)), a 5%palladium-carbon catalyst (water content: 56.8%, 4.61 g), and water (20mL) were added at room temperature, and the resulting mixture was heatedto 55° C. to 65° C. and stirred. After the mixture was stirred for about2.5 hours, the mixture was cooled to 15° C. to 25° C. Thereafter, afilter aid (KC Flock, Nippon Paper Industries) (2.03 g) was addedthereto, and the catalyst was filtered, and then, the residue was washedwith ethanol (160 mL). After concentration under reduced pressure, anethanol solution of the title compound (about 200 mL) was obtained.

1H NMR (400 MHz, CDCl₃) δ: 1.35 (3H, t, J=7.1 Hz), 1.84 (1H, broadsinglet), 2.00 (3H, s), 3.63-3.77 (4H, m), 4.27 (2H, m), 7.35-7.79 (5H,m).

Example 15(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylicacid

To the ethyl(RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate/ethanolsolution (about 200 mL) obtained by the production method of Example 14,water (80 mL) and sodium hydroxide (11.55 g (289 mmol)) were added atroom temperature, and the resulting mixture was heated to reflux. Afterthe mixture was stirred for about 5 hours, the mixture was cooled toroom temperature, and water (264 mL) was added thereto, and then, the pHof the mixture was adjusted to 5 to 6 with concentrated hydrochloricacid. After the mixture was stirred for about 40 minutes, the mixturewas cooled to 10° C. or lower, and again, the pH of the mixture wasadjusted to 3 to 4 with concentrated hydrochloric acid. After themixture was stirred for 2 to 3 hours, the deposited crystal was filteredand washed with a cooled 20% aqueous ethanol solution (120 mL). Theobtained wet crystal product was dried under reduced pressure at 40° C.,whereby the title compound was obtained (36.87 g, yield: 97.6%).

1H-NMR (CDCl₃) δ: 2.00 (s, 3H), 3.62-3.77 (m, 4H), 7.34 (d, 1H, J=7.44Hz), 7.59 (dt, 3H, J=25.63, 6.57 Hz), 7.78 (d, 1H, J=7.69 Hz).

Formulation Example 1 Capsule

The crystal (5 g) obtained in Example 8, lactose (115 g), cornstarch (58g) and magnesium stearate (2 g) are mixed using a V-type mixer, and theresulting mixture is filled in a capsule (180 mg per capsule), whereby acapsule is obtained.

Formulation Example 2 Tablet

The crystal (5 g) obtained in Example 8, lactose (90 g), cornstarch (34g), crystalline cellulose (20 g), and magnesium stearate (1 g) are mixedusing a V-type mixer, and the resulting mixture is tableted (a mass of150 mg per tablet) using a tableting machine, whereby a tablet isobtained.

Formulation Example 3 Suspension

A dispersion medium in which methyl cellulose is dispersed or dissolvedin purified water is prepared. The crystal obtained in Example 8 isweighed and placed in a mortar and kneaded well while adding theabove-mentioned dispersion medium thereto in small portions, and then,purified water is added thereto, whereby a suspension (100 g) isprepared.

The invention claimed is:
 1. A method for resolving a compoundrepresented by the following general formula (I):

[wherein R¹ represents a methyl group or a trifluoromethyl group, R²represents a hydrogen atom or a C1-C3 alkoxy group, and n represents aninteger selected from 1 to 3] into its atropisomers, comprising stirringthe compound with an optically active amine having a cinchonine skeletalformula.
 2. The method according to claim 1, wherein the opticallyactive amine is one compound selected from the group of compoundsrepresented by the following formulae:


3. The method according to claim 1, wherein the optically active amineis quinine represented by the following formula:


4. The method according to claim 1, wherein the method is performed inan organic solvent or a mixed solvent of an organic solvent and water.5. The method according to claim 1, wherein the compound represented bythe general formula (I) is the following compound (Ia):